Departments of Neurology (A.R.-D., E.H., L.S.D.), Pharmacology and Toxicology (L.S.D.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia and Department of Pharmacotherapy and Outcome Sciences (D.Y.A.S., F.M.J., J.L.M.), School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
Departments of Neurology (A.R.-D., E.H., L.S.D.), Pharmacology and Toxicology (L.S.D.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia and Department of Pharmacotherapy and Outcome Sciences (D.Y.A.S., F.M.J., J.L.M.), School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
J Pharmacol Exp Ther. 2024 Jan 17;388(2):647-654. doi: 10.1124/jpet.123.001824.
Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.
大约三分之一的海湾战争老兵患有海湾战争病（GWI），其中包括情绪障碍和抑郁症状。与部署相关的有机磷酸化合物暴露与 GWI 的发展有关。在 GWI 退伍军人中已经报道了表观遗传修饰。我们之前的研究表明，表观遗传组蛋白失调与 GWI 大鼠模型中脑源性神经营养因子（BDNF）表达降低有关。GWI 没有有效的治疗方法。氯胺酮（KET）最近已被美国食品和药物管理局批准用于治疗抵抗性抑郁症。有趣的是，BDNF 的上调是 KET 在 GWI 相关抑郁症中抗抑郁作用的基础。在这里，我们研究了 KET 对组蛋白机制的影响是否会导致 GWI 中的 BDNF 上调。雄性 Sprague-Dawley 大鼠每天皮下注射一次二异丙基氟磷酸酯（DFP；0.5mg/kg，5 天）。在 DFP 暴露后 6 个月，注射 KET（10mg/kg，腹腔内），24 小时后分离大脑。使用 Western blotting 进行蛋白质表达，使用染色质免疫沉淀方法进行表观遗传研究。 Dil 染色用于评估树突棘。我们的结果表明，抗抑郁剂量的 KET 抑制了 DFP 大鼠中组蛋白去乙酰化酶（HDAC）酶的上调。此外，KET 恢复了 DFP 大鼠中 BDNF 启动子 IV 的乙酰化组蛋白占据，并诱导 BDNF 蛋白表达。最后，KET 治疗还增加了树突棘密度，并改变了树突棘多样性，增加了 T 型，减少了 S 型树突棘在 DFP 大鼠中的比例。鉴于这些发现，我们提出 KET 的作用涉及 HDAC 表达的抑制、BDNF 的上调以及共同改善病理性突触可塑性的树突重塑，从而在 DFP 大鼠中发挥抗抑郁作用。意义声明：这项研究提供了证据支持表观遗传组蛋白途径在氯胺酮（KET）在海湾战争病（GWI）样抑郁大鼠模型中的抗抑郁作用。这种作用是通过调节 Bdnf 启动子处的组蛋白乙酰化来实现的，导致脑源性神经营养因子表达升高，并随后在海马中进行树突重塑。这些发现为考虑 KET 作为治疗 GWI 相关抑郁症的临床试验的潜在候选药物提供了依据。
